title: Essential role of the cytochrome P450 enzyme CYP2A5 in olfactory mucosal toxicity of naphthalene.
abstract: Naphthalene (NA), a ubiquitous environmental pollutant that can cause pulmonary and nasal toxicity in laboratory animals, requires cytochrome P450 (P450)-mediated metabolic activation to cause toxicity. Our recent study using a Cyp2f2-null mouse showed that CYP2F2 plays an essential role in NA-induced lung toxicity, but not in NA-induced nasal toxicity. The aim of this study was to determine whether mouse CYP2A5, abundantly expressed in nasal olfactory mucosa (OM) and the liver, but less in the lung, plays a major role in the bioactivation and toxicity of NA in the OM. We found, by comparing Cyp2a5-null and wild-type (WT) mice, that the loss of CYP2A5 expression led to substantial decreases in rates of NA metabolic activation by OM microsomes. The loss of CYP2A5 did not cause changes in systemic clearance of NA (at 200 mg/kg, i.p.). However, the Cyp2a5-null mice were much more resistant than were WT mice to NA-induced nasal toxicity (although not lung toxicity), when examined at 24 hours after NA dosing (at 200 mg/kg, i.p.), or to NA-induced depletion of total nonprotein sulfhydryl in the OM (although not in the lung), examined at 2 hours after dosing. Thus, mouse CYP2A5 plays an essential role in the bioactivation and toxicity of NA in the OM, but not in the lung. Our findings further illustrate the tissue-specific nature of the role of individual P450 enzymes in xenobiotic toxicity, and provide the basis for a more reliable assessment of the potential risks of NA nasal toxicity in humans.
authors.affiliation: Wadsworth Center, New York State Department of Health, and School of Public Health, State University of New York at Albany, Albany, New York (J.H., L.S., L.L., X.Z., F.X., J.D., X.D.); and Institute of Materia Medica, Chinese Academy of Medical Sciences & Perking Union Medical College, Beijing, China (J.H., L.S., Y.L.).
authors.forename: Jinping
authors.initials: J
authors.lastname: Hu
authors.forename: Li
authors.initials: L
authors.lastname: Sheng
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.forename: Xin
authors.initials: X
authors.lastname: Zhou
authors.forename: Fang
authors.initials: F
authors.lastname: Xie
authors.forename: Jaime
authors.initials: J
authors.lastname: D'Agostino
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Xinxin
authors.initials: X
authors.lastname: Ding
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism*; D001711:Biotransformation / Q000502:physiology; D065637:Cytochrome P-450 CYP2A6; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D000072467:Cytochrome P450 Family 2; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008861:Microsomes / Q000201:enzymology / Q000378:metabolism; D009281:Naphthalenes / Q000009:adverse effects*; D009297:Nasal Mucosa / Q000201:enzymology / Q000378:metabolism; D009831:Olfactory Mucosa / Q000201:enzymology / Q000378:metabolism*; D013438:Sulfhydryl Compounds / Q000009:adverse effects
chemical_list: D009281:Naphthalenes; D013438:Sulfhydryl Compounds; C031721:naphthalene; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C585520:Cyp2a5 protein, mouse; D065637:Cytochrome P-450 CYP2A6; D000072467:Cytochrome P450 Family 2